Suchodolski Jakub, Muraszko Jakub, Bernat Przemysław, Krasowska Anna
Department of Biotransformation, Faculty of Biotechnology, University of Wroclaw, 50-383 Wrocław, Poland.
Department of Industrial Microbiology and Biotechnology, Faculty of Biology and Environmental Protection, University of Łódź, 90-237 Łódź, Banacha 12/16, Poland.
Microorganisms. 2019 Sep 22;7(10):378. doi: 10.3390/microorganisms7100378.
is an opportunistic fungal pathogen of humans. Treatment of infections relies on azoles, which target the lanosterol 14α-demethylase (Erg11p) encoded by the gene. Our results show that targeted gene disruption of can result in resistance to ergosterol-dependent drugs (azoles and amphotericin B), auxotrophy and aerobically viable cells. Abnormal sterol deposition and lack of ergosterol in the strain leads to reduced plasma membrane (PM) fluidity, as well as dysfunction of the vacuolar and mitochondrial membranes, resulting respectively in defects in vacuole fusion and a reduced intracellular ATP level. The altered PM structure of the strain contributes to delocalisation of H-ATPase and the Cdr1 efflux pump from the PM to vacuoles and, resulting in a decrease in PM potential (Δψ) and increased sensitivity to ergosterol-independent xenobiotics. This new insight into intracellular processes under Erg11p inhibition may lead to a better understanding of the indirect effects of azoles on cells and the development of new treatment strategies for resistant infections.
是人类的一种机会性真菌病原体。感染的治疗依赖于唑类药物，其作用靶点是由erg基因编码的羊毛甾醇14α-去甲基酶（Erg11p）。我们的结果表明，erg基因的靶向基因破坏可导致对麦角固醇依赖性药物（唑类和两性霉素B）产生抗性、营养缺陷以及需氧存活的细胞。erg菌株中异常的甾醇沉积和麦角固醇的缺乏导致质膜（PM）流动性降低，以及液泡和线粒体膜功能障碍，分别导致液泡融合缺陷和细胞内ATP水平降低。erg菌株改变的PM结构导致H-ATP酶和Cdr1外排泵从PM转移至液泡，导致PM电位（Δψ）降低以及对麦角固醇非依赖性异种生物的敏感性增加。这种对Erg11p抑制下细胞内过程的新见解可能有助于更好地理解唑类药物对细胞的间接作用以及开发针对耐药感染的新治疗策略。
